Zhao Z, Bourne PE.
Eur J Med Chem
PMID:42001544
Free PMC article
Significant progress in kinase-targeted drug discovery has been made over the past two decades, with 100 FDA-approved kinase-targeted drugs and a substantial number of bioactive kinase inhibitors under preclinical study. However, given that more than 180 kinases have been implicated in disease, there remains a considerable need for continued kinase-targeted drug discovery. Covalent kinase inhibitors (CKIs) are a class of kinase inhibitors that form covalent interactions with kinase targets, valued for the potential for enhanced selectivity through anchoring nucleophiles. Here, we collate all the kinase structures from the PDB into dedicated structural kinome resources, containing: (i) the kinase domain structure database (6969 PDB structures); (ii) the kinase ligand-binding structure database (6122 PDB structures); and (iii) the kinase-CKI complex structure database (325 PDB structures). With these data, we systematically investigate the binding modes of CKIs, the fingerprint characteristics of kinase-CKI interactions, 21 types of electrophilic warheads, and 64 nucleophilic amino acids distributed in 15 corresponding spatial positions in kinase domains. We also mentioned covalent degraders and multi-warhead CKIs. Together, our results offer a comprehensive structural kinase resource and in-depth insights into CKI binding properties, supporting future kinase-targeted drug design. The databases are freely accessible at https://zhengzhster.github.io/KinaseStructureDatabase/.
Sepúlveda MS, Brown L, Capozzi SL, Cullom SC, Dick JE, Foti DJ, Franjul RH, Franklin NL, Freeman JL, Gonzalez-Canas C, Hui W, Jiang Y, Lamberti GA, Larson LQ, Malek EC, Martinez CJ, Masdari M, Meils A, de A Miranda D, Moline AK, Nieva A, Venier M, Wagner DC, Wells EM, Witkowiak KM, Xia C, Youngblood JP, Zheng H, Zhou Z, Hoskins TD.
Environ Res
PMID:42000107
Free PMC article
Per- and polyfluoroalkyl substances (PFAS) are persistent contaminants of global concern, yet integrated, multi-compartment assessments at the regional scale remain limited. Here, we present a cross-media evaluation of PFAS occurrence, distribution, bioaccumulation, and exposure across Indiana, a midwestern United States state characterized by mixed industrial, urban, and agricultural land use. Detection relied on a combination of targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) and emerging electrochemical sensor approaches to capture both known and previously unmonitored PFAS. Atmospheric deposition data indicate the presence of both legacy and emerging PFAS, including ultra-short-chain compounds that dominate wet deposition profiles. Analysis of 473 Indiana public water systems (2021-2024) revealed detectable PFAS in 15.4% of treated drinking water systems, with 1.9% exceeding proposed maximum contaminant levels; larger systems and areas with higher proportions of minority residents were more likely to report detections. Statewide fish monitoring (n = 940 samples, 44 species) demonstrated substantial bioaccumulation, with perfluorooctanesulfonic acid (PFOS) comprising ∼69% of total PFAS burden and multiple counties exceeding consumption advisory thresholds. Preliminary human serum biomonitoring confirmed widespread exposure to a broad spectrum of legacy and replacement PFAS. Bench-scale treatment tests conducted in the state showed high removal efficiencies for selected PFAS using activated carbon under pre-breakthrough conditions, while evaluation of fluorine-free firefighting foam alternatives revealed performance trade-offs relative to PFAS-based formulations. Collectively, these findings demonstrate that PFAS contamination in Indiana spans atmospheric, aquatic, biological, and human compartments, highlighting interconnected exposure pathways and the need for integrated monitoring and mitigation strategies. This statewide assessment provides a model for evaluating PFAS contamination in regions with diverse land use and industrial activity.
Chu F, Gao L, Tang H, Luo J, Li W, Zhou S, Zhuo F, Wang X, Feng H, Pan Y.
Anal Chem
PMID:41989759
Free PMC article
An in-depth study of electrochemistry (EC) requires a sensitive and real-time monitoring platform. Herein, we report a bubble extraction ionization electrochemical mass spectrometry (BEI-EC-MS) platform for monitoring the reaction products and transient intermediates in the EC reactions. Compared with previous online EC-MS methods, BEI-EC-MS employs in situ soft ionization within the electrolytic cell, eliminating the need for additional voltages during the reaction monitoring process. The ascending bubbles effectively extract and concentrate compounds from both the surface of the EC electrode and electrolyte, enabling long-term monitoring in both positive and negative MS modes. Monitoring experiments of aniline (ANI) EC polymerization verified the platform performance and successfully captured short-lived radical intermediates. The platform was then used to monitor the long-term EC degradation of the pollutants dinotefuran (DNT), rhodamine B (RhB), and perfluorooctanoic acid (PFOA). A series of intermediates and products were characterized by using BEI-EC-MS, including various radical ions measured for the first time, providing pivotal evidence for the degradation mechanisms of these reactions. We anticipate that our approach will not only provide new protocols for monitoring EC reactions and assist in conducting mechanistic studies but also be readily adaptable in conventional electrochemical laboratories with the mere addition of a bubble generation device.
McGrath J, Royle O, Thorpe A, McCauley JI, Ueland M, Kabakova I, Chen H, Clases D, Oliver BG, Bordin DM.
Anal Bioanal Chem
PMID:41991746
Free PMC article
E-cigarettes are promoted as a safer alternative to conventional tobacco, yet emerging evidence indicates they may expose users to harmful metals. While prior research has focused on nicotine and organic constituents, the bioaccumulation and spatial distribution of toxic metals in lung tissue remain poorly understood. In this study, a multi-platform analytical approach combining ICP-MS, GC-ICP-MS, GC-MS, and LA-ICP-MS/MS was employed to characterise the elemental and organic composition of refillable e-cigarette liquid and its corresponding aerosol, and to assess metal accumulation in murine lung tissue following short-term exposure. Balb/c mice (7 weeks, n = 8 per group) were exposed to nicotine-containing e-cigarette aerosols (8, 16, or 32 puffs; 30 min, twice daily for 4 days) or ambient air (control). Results showed that multiple toxic metals and organometallic species were detected in both e-liquid and aerosol, including species of Al, Ni, Cu, As, Br, Sn, and Hg. Elemental bioimaging of murine lungs found heterogeneous focal accumulation patterns in lung tissue, with increased Cu, significantly elevated Ni and Pb, and significantly reduced pulmonary Fe concentrations (p ≤ 0.005). Metal distribution patterns were exposure-related but not strictly dose-dependent, indicating a complex deposition and clearance mechanism. This study provides the first evidence of metal-containing (organometallic) species in e-cigarette aerosols and exposure-associated metal accumulation in murine lung tissue. These findings reinforce the need for further mechanistic and longitudinal investigations to assess the health risks associated with chronic vaping exposure.
Sierra-Serrano B, Sturabotti E, Cardo L, Prato M.
Nanoscale
PMID:41811161
Free PMC article
Carbon dots (CDs) doped with iron are valuable nano-contrast agents (nCAs) for magnetic resonance imaging (MRI) owing to their optimal compatibility, stability and interesting relaxivity, even at ultra-high fields (UHF-MRI, ≥7 T). Moreover, they represent suitable alternatives to Gd-based contrast agents frequently associated with moderate toxicity. Notably, UHF-MRI offers enhanced spatial resolution and improved signal-to-noise ratios, challenging some limitations encountered for standard MRI of vascular tissues, brain or applications demanding high sensitivity. The design of nCAs for UHF-MRI is not straightforward due to their tendency to show predominant T 2 -character at high fields, hence leading to image darkening and resolution loss. For this reason, we propose novel Fe-doped CDs (Fe@CDs) working as dual mode T 1 / T 2 nCAs for UHF-MRI; as a grounding concept, our synthesis was supported by stringent purification, a practice extremely overlooked in the CD field. Pure Fe@CDs (Fe content 3.7%) were isolated from fluorescent molecular-like subproducts and uncoordinated metals by size exclusion chromatography (SEC-HPLC); the particles showed good dimensional homogeneity (AFM = 5.0 ± 2.2 nm; TEM = 4.0 ± 1.3 nm), with blue centered and typical wavelength-dependent fluorescence. The structure of Fe@CDs was enriched in carboxylic moieties, enabling stable coordination of iron (in a mixed +2/+3 oxidation state), and optimal in vitro safety was observed on A549 cell line at the highest concentration investigated (500 mg mL -1 ). Fe@CDs presented low r 2 / r 1 ratios at high fields, behaving as T 1 / T 2 dual-mode probes ( r 2 / r 1 @7 T = 2.78 and r 2 / r 1 @11.7 T = 3.23); notably, the magnetic properties remained almost unaltered for 8 days in water and cellular medium. Our results provide a combined and wide approach for synthesizing artifact-free Fe-doped CDs with potential in advanced UHF-MRI techniques.
